Introduction:

PSMA-PET/CT-detected mesorectal lymph node (MLN) metastases are present in 11% of biochemically recurrent prostate cancer patients in the post-radical prostatectomy or radiotherapy settings. The biologic significance and clinical implications of these lesions remains unknown. Whether these novel findings represent classical ‘stage migration’ or advanced stage disease associated with adverse clinical outcomes remains unknown. The study objectives were thus to compare the oncologic outcomes of biochemically recurrent patients with MLN metastases to those with other ‘classical’ sites of metastases, using the primary outcome of time to development of castration-resistant disease, and evaluate clinical responses to treatment.

Methods:

This is a retrospective analysis of biochemically recurrent prostate cancer patients (post-radical prostatectomy and/or radiotherapy) with a positive ¹⁸F-DCFPyL-PSMA-PET/CT that was performed at a tertiary center between December 2018 and February 2021. The study patients were prospectively enrolled in the PSMA-PET for Recurrent Prostate Cancer (PREP) provincial registry.

We evaluated the association between site of most advanced disease (mesorectal-only versus other sites) and development of castration resistance using a multivariable Cox model, adjusted for PSA level at PSMA-PET/CT and biopsy Grade Group. The site of most advanced disease was defined in the following ascending order: prostatic fossa-only residual/recurrent disease, MLN metastases, pelvic lymph node disease (cN1), non-regional nodal disease (cM1a), bone metastases (cM1b), and visceral organ metastases (cM1c). 

The secondary study objectives were to evaluate oncologic outcomes (prostate-specific antigen [PSA] decrease by 50% [PSA50] and freedom from androgen deprivation therapy [ADT]) in patients with MLN-only metastases treated with metastasis-directed therapy (MDT).

Survival analysis with Kaplan Meier curves was performed for time-to-event outcomes.

Results:

The cohort included 301 patients with PSMA PET-positive disease, of whom 71 had mesorectal nodal disease (44 had mesorectal-only disease). At a median follow-up of 36 months, patients with mesorectal nodal-only disease had equivalent rates of castration resistance development, compared to patients with prostatic fossa-limited disease (HR=0.99, p=0.88). Sixteen patients with mesorectal nodal disease underwent metastasis-directed therapy. A PSA50 response was observed in 5/10 patients with mesorectal nodal-only disease and 2/6 for those with additional pelvic nodal disease. All patients without a PSA50 response were started on hormones, with no castrate-resistance development to date. The median hormone-free survival was 28 months.

Conclusion:

Biochemically recurrent patients with mesorectal nodal-only disease on PSMA-PET/CT have identical rates of castrate resistance development, compared to patients with prostatic fossa-limited residual/recurrent disease, and have promising clinical responses with metastasis-directed therapy. Strong treatment recommendations are limited by the small sample size and short-term follow-up. Further analysis with longer follow-up and a larger sample size, including strict criteria for MDT selection, will be needed to confirm these findings and substantiate any strong treatment recommendations.

Funding: N/A